The epsilon4 allele of apolipoprotein E (apoE) increases the risk of developing Alzheimer's disease (AD). Data from both in vitro and in vivo studies suggest that a major reason for the involvement of apoE in AD is related to its ability to modify the deposition and conformation of amyloid-beta protein (Abeta). Various studies have shown strong correlations between AD pathogenesis and the level and structural conformation of Abeta. While Abeta is normally present in a soluble form, it is converted into an insoluble fibrillar form with high beta-sheet content in AD. The transition of Abeta into insoluble aggregates including fibrils is thought to drive the early progression of AD. The proposed research will utilize a transgenic mouse model of AD to study the affects that apoE has on the structural organization of Abeta and how different structural forms of Abeta influence its interactions with neurons and its neurotoxicity. The specific aims of the proposed research are: 1) to characterize the ultrastructure of Abeta deposits in APPv717F transgenic mice in the presence and absence of apoE; 2) to characterize the neurotoxic properties of Abeta fibrils in the absence of apoE; and 3) to analyze the cellular responses elicited by different structural forms of Abeta in real-time.